AIDS has been as puzzling to researchers as it has been devastating to the infected population.
AIDS is a contagious disease that destroys the body's ability to fight infection, and is transmitted through blood and other bodily fluids--mainly during sexual intercourse. An individual may contract AIDS from an AIDS carrier who is not suffering from the illness and may even be unaware of the infection. There is no known cure for AIDS and sufferers typically die within three years of contracting the disease. While reports of promising anti-AIDS drugs surface frequently, test results have so far been disappointing. One drug after receiving much attention was proven ineffective, if not actually harmful.
Although many drugs have shown promise against AIDS, none have been shown to be capable of curing AIDS once it has been contracted. Amer. Pharm. NS 26-36 (Jan.) 1986, Amer. Pharm. NS 25:14 (July) 1986. Similarly, prospects for an AIDS vaccine have been found to be poor. Most estimates have been that it will take researchers ten years to devise a way to immunize high-risk groups. Meanwhile, the disease continues to spread at an alarming rate. Although the etiology of AIDS is poorly understood the symptomology is similar to other immune system anomalies.
Primary immunodeficiency is a rare, but devastating, condition in which there is a partial or total collapse or absence of one or more classes of immune responses. It is typified by recurrent or chronic life-threatening infections and by the necessity for its victims to live in rigorously controlled, sterile conditions. There is no existing treatment other than isolation of the patient from all potential sources of infection.
Secondary immunodeficiency, in which the immune system function is reduced, may appear as a result of age, disease or the use of certain therapies, such as cytostatic radiotherapy or chemotherapy for cancer. Patients whose immune system function is reduced are vulnerable to both viral and other infections, and treatment of such infections may be complicated and/or protracted.
Acquired immune deficiency syndrome (AIDS) is a recently identified syndrome in which a person's immune system after functioning normally ceases to function adequately. While AIDS resembles somewhat the clinical pathology of secondary immunodeficiency, it alone is uniquely characterized by a reduced ratio of helper to suppressor T-cell subsets, as explained below.
Because of the breakdown in the immune system, individuals suffering from AIDS are highly vulnerable to infections resulting in a high mortality from opportunistic infections and Kaposi's sarcoma. See, e.g. "Immunocompromised Homosexuals" (Editorial) Lancet 1981; ii: 1325-6; Center for Disease Control, "Epidemiological Aspects of the Current Outbreak of Kaposi's Sarcoma and Opportunistic Infections", N. Engl. J. Med. 1982, 306: 248-52; Gerstoft et al., "Severe Acquired Immunodeficiency in European Homosexual Men", Br. Med. J. 1982, 285: 17-19. The two year mortality rate has been reported to be as high as 80%.
The etiology of AIDS is ascribed to a human T-lymphotropic retrovirus (HTLV or LAV, or human immunopathic virus [HIV]) the discovery of which has stimulated an active search for effective anti-retroviral chemotherapeutic agents. As yet no agents have been shown to be truly effective in curing HIV infection or reversing the underlying immunodeficiency.
To understand the hypothesized effect of the HIV virus on the human body, it is first necessary to have a basic understanding of the body's normal immune system. The human body's mechanisms for responding to invading infectious organisms are extremely complex. The principal immune reaction depends upon cells, called lymphocytes, which recognize the need for, and initiate, appropriate responses. Lymphocytes are broadly classified into two groups, B and T cells, and in turn both groups are further categorized into a diversity of types or subsets, especially the T cells.
Functionally, there are two kinds of T cells, effector T cells, which cause various immune reactions and regulatory T cells which control the development of effector lymphocytes, both of the T and B type. The regulatory T cells may also be broken into three subsets, T regulatory, T helper, and T suppressor cells. The T helper cells stimulate the proliferation of B cells and T effector cells which are responsible for directly combating infection, whereas T suppressor cells block the effect of the T helper cells.
In a human with normal immune responses, the ratio of T helper cells to T suppressor cells is approximately 2:1. However, uniquely, in a patient suffering from AIDS, the ratio of T helper cells to T suppressor cells is substantially reduced, usually to a point at which the number of T suppressor cells exceeds the number of T helper cells. The exact reason for this phenomenon is not known. However, it has been found that the HIV virus specifically invades and destroys T helper cells.
HIV is an RNA retrovirus. Other known retroviruses induce sarcomas, leukemias, lymphomas, and mammary carcinomas in animals. The unique aspect of a retrovirus is that it reproduces through a DNA intermediate. The progeny RNA is then generated through regular transcription of the DNA intermediate. The DNA intermediate is produced via a polymeric enzyme called reverse transcriptase. Thus, the fact that HIV is a retrovirus can be confirmed by the presence of the viral reverse transcriptase.
The fact that the HIV virus is present within a host can also be determined by analyzing for the presence of the viral protein antigens p24 and p17. The presence of such antigens in cells indicates the presence of the HIV virus.
Dermostatin and dermostatin A and dermostatin B are carbonyl conjugated polyene macrolide antimicrobial agents. Dermostatin complex which contains both dermostatin A and dermostatin B has been used as an effective agent for the treatment of fungal infections in humans. Heretofore, dermostatin A and dermostatin B have not been isolated and separated from the dermostatin complex. Amphotericin B is the drug of choice for many systemic fungal infections in humans for many years. The antifungal activity of amphotericin B is at least in part dependent upon its binding to a sterol moiety in the cell membrane. By virtue of this interaction, channels, or pores are formed in the cell membrane allowing leakage of a variety of small molecules. However, effects of amphotericin B on the permeability of sterol-free membranes have suggested that additional mechanisms may be involved.
Other polyene antibiotics, such as nystatin, natamycin, hamycin, aureofungin and candicidin, have been known and used clinically for many years. More recently, dermostatin has been found to have activity against fungi and to be useful in the treatment of certain fungal infections.